JP2000510844A - Method of treating type I hypersensitivity using monophosphoryl lipid A - Google Patents

Abstract

  (57) [Summary] Disclosed are methods and compositions for treating type I immunoglobulin E (IgE) -dependent hypersensitivity by administration of monophosphoryl lipid A (MLA) or 3-deacylated monophosphoryl lipid A (3D-MLA). Administration of MLA or 3D-MLA alone or in combination with an allergen to a patient with type I hypersensitivity decreases the level of total IgE or allergen-specific IgE and increases the level of IgG antibodies in the patient. MLA and 3D-MLA can be administered as part of a desensitization therapy or as a component of a prophylactic vaccine to prevent type I hypersensitivity reactions.

Description

DETAILED DESCRIPTION OF THE INVENTION           Method for treating type I hypersensitivity with monophosphoryl lipid A Technical field   The present invention relates to monophosphoryl lipid A or 3-phosphoryl lipid A. 3-deacylated monophosphoryl lipid A alone Or type I immunoglobulin E when administered to patients in combination with an allergen (IgE) -dependent hypersensitivity.Background of the Invention   Type I IgE-dependent hypersensitivity represented by atopic allergic reaction is caused by environmental antigens (A Allergens), which occurs in certain individuals who overproduce IgE antibodies. That Lugie affects a significant number of people worldwide, including more than 400,000 people coming to Japan. You. Allergic diseases include rhinitis, asthma and atopic dermatitis. one Common environmental allergens include pollen, mold, food, drugs, house dust mites and animals Contains sexual scales.   In recent years, there has been considerable progress in understanding the immune mechanisms underlying type I IgE-dependent hypersensitivity reactions. Has been done. The molecular basis of type I hypersensitivity involves complex parts of the immune system. Interactions are involved. These complex interactions in the allergy cascade The action offers many promising sites for therapeutic intervention. In general, I Type sensitivity is understood to be due to the formation of allergen-specific IgE. Allele Gen-specific IgE passively interacts with mast cells in tissues or basophils, mainly in blood To combine. Allergic reactions occur on mast cells or basophils, and A number of histamine-containing cells that bind to IgE, possibly on other cells Topical application of allergens, injection, oral ingestion to release mediators. Or caused by exposure by inhalation. These mediators can cause asthma, edema and It causes various clinical symptoms such as inflammation and inflammation. In some individuals, the symptoms are particularly severe May cause anaphylactic shock or immediate treatment Failure to do so can result in death. Clinical symptoms include antihistamines, cromolyn and Most commonly treated with a variety of drugs, including and corticosteroids It is.   Allergen immunotherapy in the form of desensitization regimen , It is widely used to treat individuals with clinically significant type I hypersensitivity reactions. To achieve a clinically diminished response or desensitization to the allergen, Over time, the individual has been inoculated with a small amount of an offending allergen. It is. Typically, the initial dose of allergen is very low, reaching the so-called maintenance dose. And gradually continue for months or years. This Ip immunotherapy is based on atopic allergies (hay fever, insect sting allergy, As well as some forms of asthma) , This has significant drawbacks. Of particular concern is the administration of allergens. There is a risk of severe allergic reactions with administration. in this way The inherent risk of severe allergic reactions such as anaphylactic shock Due to the risk, the treatment regimen will initially be very small. Use allergens and make sure that the dose of allergen is gradually increased. However, the results obtained with currently used treatments are As a result, the treatment period is longer and the number of injections required to achieve satisfactory results is Increase. Therefore, the overall success of immunotherapy is limited and clinically The goal of management is to control allergy cascade by immunological techniques such as allergen immunotherapy. Is often directed at controlling symptoms associated with medication rather than controlling This is Shibashi. In addition, in patients with persistent allergic reactions, The results obtained with use are often mixed. Allergen immunotherapy is Activation of blocking antibodies (mainly IgG) that neutralize rugen, and host reaction from TH2 to TH1 Closer response, IgE antibodies to specific allergens injected A specific anti-idiotypic antibody Elicits complex immunological responses, including stimulating activation and reduced allergic inflammatory response I do.   Try to preserve or enhance the benefits of immunotherapy while reducing the negative aspects Efforts have led to a variety of alternative treatment approaches. These alternative hands The method includes changing the dosage form of the allergen administered to individuals with type I hypersensitivity reactions (refor mulation). Such dosage forms include alum-precipitated allergen extract , Chemically modified allergen preparations, allergens encapsulated in liposomes, And allergens used in combination with other adjuvants. US Patent 5,013,55 No. 5 describes the use of liposomes containing allergens. US Patent 4,9 No. 90,336 describes a multiphase sustained release delivery system using microcapsules. It is listed. Oral therapy in which an allergen is administered in a solid support is disclosed in U.S. Pat. No. 5,244,663. Alum is currently available from the US Food and Drug Administration (FDA) It is the only adjuvant that has been approved. However, in animal models, Has been shown to enhance rather than decrease IgE production, which is desirable. Not good. Saponins (US Pat. No. 4,432,969) for use in desensitization therapy And other adjuvants such as alkyl esters of tyrosine have also been described. So Other therapeutic approaches include modified peptides (US Pat. No. 5,073,628) or IL-4 receptor Body antagonists (Patent Cooperation Treaty, WO 93/15766). This These alternative approaches include lack of allergen specificity or unacceptable reactions. There are potential limitations, such as the risks posed. Some specific allergen immunotherapy Has proven to be effective, but this is not consistently safe. Or all patients or allergens are successful Nor. Allergen immunotherapy as currently used remains controversial. It is a form of treatment. Alternative or Complementary Effective Allergy Therapy Strategies Is in continuous demand.Summary of the Invention   The present invention provides a method of treating or preventing type I IgE-dependent hypersensitivity in an individual, And compositions for such treatment. The present method provides an effective amount of Nophosphoryl lipid A (MLA) or 3-deacylated monophosphoryl lipid A (3D-ML A). Surprisingly, when administered to individuals with type I MLA or 3D-MLA reduces total or allergen-specific IgE while And, preferably, to induce the production of IgG antibodies. IgG antibodies A blocking antibody that reduces allergic reactions. MLA or 3D-MLA is the right treatment An effective amount alone in a suitable vehicle may be administered in accordance with the regimen. Together with allergens as part of desensitization therapy for allergen-specific type I hypersensitivity It may be administered. These compounds will benefit from IgE-dependent allergies. Be added to the vaccine composition to enhance the effectiveness of the vaccine in addition to To do it can. Administration of MLA or 3D-MLA may cause the individual to be exposed to allergens Potentially serious and potentially lethal in individuals with hypersensitivity Reduces the risk of a rugi reaction occurring.   The present invention also relates to an effective amount of MLA or 3D-MLA alone contained in a suitable solvent. Or with one or a mixture of allergens, I Also included are pharmaceutical compositions for treating type hypersensitivity. Or MLA or 3D-MLA With the allergen or mixture of allergens in a continuous but independent form May be administered.Detailed description of the invention   Administration of MLA or 3D-MLA to an individual suffering from type I Modulates allergic response to any allergen that is sensitive to That has been found.   Type I hypersensitivity reactions are most commonly observed in what is commonly referred to as "hay fever." Anaphylaxis that can lead to death from relatively mild reactions that induce symptoms such as Histamine released in the body varies from severe reactions such as the Sea reaction. It is caused by pharmacologically active substances, including: These substances are allergen-mast IgE cells that are likely also fixed to cells, basophils and possibly other cells Released from mast cells or other cells after binding to an antibody known as You. In patients with type I hypersensitivity, ragweed pollen, cat scales, house dust mites What substances or other substances that cause their allergic reactions or diseases It has been observed that the amount of IgE antibody against is abnormally high.   By administering an effective amount of MLA or 3D-MLA formulated in a suitable solvent, The titer of gE-class antibodies is significantly reduced, thereby causing histamine or other transmission. Low amount of IgE antibody that can attach to mast cells, effectively reducing delivery of delivery substances It has been found to go down. Without being bound by any particular theory, Administration of MLA or 3D-MLA stimulates production of allergen-specific IgG and production of IgE antibodies It is believed to reduce. Subsequently, IgG binds and neutralizes allergen And essentially block IgE-allergen interactions that cause hypersensitivity reactions. It is. Decrease in IgE causes the individual to have an allergic allergic reaction Tendency become weak.   The present invention relates to administration of a pharmaceutical composition comprising an effective amount of MLA or 3D-MLA depending on the patient. Stimulates IgG antibodies more preferentially than IgE antibodies, thereby reducing desensitization therapy. Allergens to any allergen without the need for allergen administration as part Improved than current therapies, which are thought to substantially reduce energy response Provide an alternative. Pharmaceutical composition comprising an effective amount of MLA or 3D-MLA for desensitization therapy If co-administration of the allergen with the appropriate allergen May reduce the risk of developing an allergic reaction to the administration of. This is a book The invention requires less desensitizing allergen or fewer injections Thought to be achieved by being able to enable changes in allergen immunotherapy Can be   An effective amount of MLA or 3D-MLA administered with a bacterial vaccine also provides IgE. It is thought that it promotes the production of IgG while reducing it. The IgG produced is It is believed to be specific for bacterial antigens in vaccines that enhance the effect of the vaccine. Childhood Prepared for primary immunization of infants, a normal procedure for preventing infection of Vaccines that contain MLA or 3D-MLA are not It is thought to reduce the tendency to become allergic to common allergens.   As used herein, "treatment" of type I hypersensitivity refers to a beneficial or desirable clinical A method for obtaining results. Desirable clinical outcomes include prevention of symptoms Or mitigation, but is not limited to these.   Active compounds for treating individuals with type I hypersensitivity according to the invention are mono- Phosphoryl lipid A (MLA) and 3-deacylated monophosphoryl lipid A (3D-MLA ) Is selected from the group consisting of purified detoxified e ndotoxin). Both MLA and 3D-MLA are known and are described in detail herein. There is no need to explain. For example, published on March 13, 1984, Livi Immunochem -Monophosphoryl transferred to Research (Ribi ImmunoChem Research Inc.) See U.S. Pat.No. 4,436,727, which discloses lulipid A and its preparation. No. Myers, also transferred to Livi Immunochem Research No. 4,912,094 and Reexamination Certificate B1 4,912,094 to Acylated monopho 1 embodies sphoryl lipid A and a method for its preparation. MLA and 3D-M The disclosure of each of these patents relating to LA is incorporated herein by reference. It is.   Details not pre-incorporated by the referenced patent are not mentioned, but are not The monophosphoryl lipid A (MLA) used is a powerful but extremely toxic It is derived from lipid A, a component of the intestinal bacterial lipopolysaccharide (LPS), which is an epidemic regulator.   Edgar Ribi and colleagues describe purified detoxified endotoxin (RDE) and The first production of monophosphoryl lipid A (MLA) was realized. MLA Endotoxin extract (LPS or Lipid A) in an inorganic acid of moderate strength (0.1N HCl) for about 30 minutes It is generated by refluxing. By this treatment, reducing end glucosamine Results in the loss of the phosphate moiety at position 1.   At the same time, core carbohydrate is added to the non-reducing glue during this process. Cosamine is removed from position 6. The resulting product (MLA) is pyrogenic, topical Schwartzman reactivity and chick embryo 50% lethal assay Toxicity (CELD₅₀), Such as endotoxin activity normally associated with endotoxin starting materials Presents a significant decrease in gender level. However, unexpectedly, this is And LPS function as immunomodulators.   Another detoxified endotoxie that may be used in the practice of the present invention This is called 3-deacylated monophosphoryl lipid A (3D-MLA). 3D-MLA is Known as described in U.S. Patent No. 4,912,094, Reexamination Certificate B1 4,912,094 From the MLA molecule under conditions that do not deleteriously affect other groups. A B-hydroxymyristine acyl residue, an ester linked to the 3-position of Samin, was selected. It differs from MLA in that it is selectively removed. 3-Deacylated monophosphoryl lipid A is , Ribi ImmunoChem Research Inc., Hamilto n, available from Montana 59840.   MLA and 3D-MLA molecules have a number of fatty acid substitution patterns, Complexes of sil, hexaacyl, pentaacyl, etc. with fatty acid chains of various lengths Or a mixture. Accordingly, the present invention includes various forms, including mixtures thereof. state MLA and 3D-MLA are included. -Lipid A illustrated in the '094 patent Is used for 3-deacylation of heptaacyl lipid A derived from S. minnesota R595. Therefore, it corresponds to the obtained product. Other fatty acid substitution patterns are described in this disclosure. Included. Its essential feature is that the material is 3-deacylated.   The modified 3D-MLA used in the present invention is a single 3D-MLA from position 3 of the lipid A backbone. Subjecting MLA to alkaline hydrolysis under conditions in which only fatty acids are lost It is thus prepared. B-hydroxymyristine fatty acid at position 3 Then, the reactivity becomes very high. For complete 3-deacylation of lipid A, It is only necessary to always perform a weak alkali treatment. Other ester bonds inside lipid A Some more intense conditions are required for the hydrolysis of Selectively select these materials in position 3 without significantly affecting the rest It is possible to deacylate. 3-position B-hydroxy myristyl ester bond It is unknown at present why the fatty acids are so sensitive to alkaline solvents is there.   Several procedures for alkaline hydrolysis are known, but B-hydroxy Select conditions that do not cause further hydrolysis beyond the ester bond with the listin fatty acid It is important to.   Generally, the hydrolysis can be carried out in an aqueous or organic solvent. . In the latter case, methanol (alcohols), dimethyl sulfoxide (DMSO ), Dimethylformamide, chloroform, dichloromethane, etc. These mixtures are included. Mixtures of water with one or more of the above organic solvents Can also be used.   Alkali base selected from various hydroxides, carbonates, phosphates and amines can do. Exemplary bases include sodium hydroxide, potassium hydroxide, charcoal Inorganic salts such as sodium acid, potassium carbonate, sodium bicarbonate, potassium bicarbonate Groups and organic bases such as alkylamines; diethylamine, triethyl Examples include, but are not limited to, amines.   The pH in aqueous solvents is typically between about 10 and 14, and between about 12 and 13.5. Is a preferred range. The hydrolysis reaction is typically from about 20 ° C to about 80 ° C. And preferably at a temperature of about 50 ° C to 60 ° C for a period of about 10 minutes to about 30 minutes. It is just implemented. For example, hydrolysis is performed in a 3% aqueous solution of triethylamine at room temperature. (22 ° C. to 25 ° C.) for 48 hours. Temperature and hydrolysis The only requirement for time selection is that only B-hydroxymyristin in position 3 is excluded. Deacylation as would be done.   In practice, particularly desirable methods of hydrolysis include lipid A or monophosphoryl. Dissolve Lulipid A in chloroform: methanol 2: 1 (v / v) and add 0.5M of pH 10.5 Na_TwoCO_ThreeSaturate this solution with an aqueous buffer consisting of May include flash evaporation of the solvent under reduced pressure (approximately 100 mmHg). It is clear. The resulting material undergoes selective deacylation at position 3. I am. Perform this process using any of the inorganic bases listed above You can also. In some cases, before saturating with aqueous buffer, add It is considered desirable to add a phase transfer catalyst such as rabutylammonium bromide. available. In addition to MLA and 3D-MLA generated as described above, May use MLA and 3D-MLA generated by a semi-synthetic process.   MLA or 3D-MLA can be used to detect IgE antibody levels when administered to warm-blooded animals in a safe and effective dose. Lowers the bell, thereby causing a severe allergic reaction to allergen exposure. It has been observed that the risk of response occurs.   The method of the present invention provides a pharmaceutically effective carrier for a warm-blooded animal, preferably a human. Includes detoxified endotoxin selected from the group consisting of provided MLA and 3D-MLA It embodies the administration of a pharmacologically effective amount of the composition. Pharmaceutical as used herein The term effective amount elicits a pronounced response in the patient, i.e. By reducing the total amount and / or increasing the total amount of IgG antibodies, Partial or complete blockade of clinical symptoms of an allergic reaction due to exposure is achieved Means a sufficient amount of the composition to Administration can be via any suitable route. Depending on the allergen, the individual and the desired clinical outcome. It is. Apply MLA or 3D-MLA to mucosal surface by oral, intranasal or inhalation It can also be administered via The parenteral route, i.e., intraperitoneally or intramuscularly, A lesser degree of preference can be used. The preferred route of administration is subcutaneous is there.   The exact dose will depend on the particular MLA or 3D-MLA used, the route of administration, the pharmaceutical composition You And may vary from patient to patient. For example, the most preferred route of administration (subcutaneous) If used for a typical 70 kg adult patient, the active ingredient (ML A or 3D-MLA) from 1 to about 250 micrograms, preferably from about 25 to about 5 Up to 0 microgram.   The methods of the invention contemplate single or multiple doses depending on the particular situation. Preferred routes of administration and regimens for any case include relatively It can be confirmed by routine experiments.   As used herein, the term "pharmaceutically acceptable carrier" refers to the active ingredient. A vehicle that does not interfere with the medicinal effects and is not harmful to the patient to whom it is administered. Pharmaceutical Carriers that are acceptable for oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes , Microbeads, microsomes or alum.   An example of a preferred carrier for subcutaneous use is United States Pharmacopeia (USP) Water for Injection Contains phosphate buffered saline (PBS) and 0.01-0.1% triethanolamine You. One significant point to point out about the carrier is that MLA and 3D-MLA Since normal salt solution precipitates in normal saline solution, It is clear that it must not be used with light active ingredients. medicine A parenteral solvent that is chemically acceptable is a 5 micron filter without removing the active ingredient. A solution of the active ingredient according to the invention, such that the solution or dispersion can be filtered through a filter Or such that a dispersion is provided.   Carriers for intramuscular use include 10% USP ethanol, 40% glycol propylene And an acceptable isotonic solution equilibrium solution such as 4 and 5% dextrose. M In saline if the solubility of LA or 3D-MLA is stabilized in liposomes ML encapsulated in liposomes is not expected to precipitate active ingredient Alternatively dissolve A or 3D-MLA in normal saline for intramuscular use It is also possible.   Examples of carriers for administration via a mucosal surface will vary depending on the particular route. Oral Pharmacokinetic mannitol, Starch, lactose, magnesium stearate, sodium saccharide, Cellulose, magnesium carbonate, etc. can be used, among which mannitol preferable. If administered intranasally, use polyethylene glycol or glyco , Sucrose and / or methylcellulose, and benzalkonium chloride Preservatives such as EDTA and EDTA can be used, but polyethylene glycol is preferred. For administration by inhalation, suitable carriers are polyethylene glycol or Or glycols, methylcellulose, dispensing agents and As a preservative, polyethylene glycols are preferred.   MLA or 3D-MLA in the appropriate vehicle alone or together with other active ingredients May be administered at any time. For example, in a preferred embodiment, MLA or 3D-MLA is Can be administered together with the allergen. Accurate schedule for simultaneous administration Joule will depend on the patient, the severity of the patient's hypersensitivity and the route of administration. Can be Generally, the treating physician will make a treatment plan based on these factors. And the treatment plan is ultimately relatively routine in order to achieve the desired result. Determined by experiment.   Including MLA or 3D-MLA as part of desensitization therapy to treat type I hypersensitivity If a composition is co-administered with an allergen, such a composition may be Between 24 hours before and 24 hours after the administration of Rugen, preferably allergen administration It may be administered from one hour before to the same time point.   "Allergen" is any substance that can cause a type I hypersensitivity reaction . Typical allergens include pollen, mold, food, animal dander or their secretions Includes without limitation objects, smoke and insects, their venoms or secretions. Type I excess They can be administered alone or as a mixture, depending on the nature of the sensitivity. Allergens may be chemically or physically modified. Such a modified array Rugen or allergen derivatives are well known in the art. Examples include Includes, without limitation, peptide fragments, conjugates or polymerized allergen derivatives.   The amount of allergen to be administered can be empirically determined and depends on the individual Depends on the sensitivity or desired clinical outcome. Generally, cure of desensitization The treatment plan initially includes periodic administration of small doses of allergens, followed by the course of treatment. To reach the specified (planned) upper limit or Resists exposure to such allergens without apparently harmful allergic reactions Gradually increase to the point where it can be obtained. Specific treatments can be tailored to individual patient needs. It is often adjusted accordingly. Aspects and potential advantages of the present invention are that Cause a significant reduction in the level of allergens given and / or the number of injections And that can shorten the duration of desensitization therapy. further, Significantly reduce the levels of allergens administered to particularly sensitive individuals Risk of severe allergic reactions to allergen administration Is thought to decrease.   The progress of the immunotherapy can be monitored by clinically acceptable diagnostic tests. this Such tests are well known in the art and the level of symptoms recorded in a daily diary Skin testing and specific IgE antibodies and levels of adjuvant therapy And / or in vitro serologic tests for IgG antibodies.   The following examples are given for the purpose of detailed illustration, and illustrate the compositions and compositions of the present invention. And does not limit any of the methods. Rats and mice presented herein The model is representative of warm-blooded animals, including events related to other warm-blooded animals, including humans. It is correlated.                                 Example I   This example demonstrates the level of IgE in a model designed to induce an IgE response. 2 shows the action of 3D-MLA to reduce the concentration.   BALB / c or C57B1 / 6 mice were injected with 100 μg ovalbumin (OVA) (Sigma Chemi cal) + 1 μg pertussis toxin (obtained from Research Products Intl.) Immunization treatment with 3% oil-in-water emulsion ± 50 μg 3D-MLA was performed subcutaneously. Primary immunity A booster treatment was performed 14 days after the immunization treatment. Blood is collected from mice at various times ELISA (reagents were obtained from Southern Biotechnology Assn. Inc.). Serum quantification for total IgE was performed using a standard curve for serum IgE.   Referring to Table 1 below, when ovalbumin and 3D-MLA were co-administered, blood The data show that clear total IgE levels are significantly reduced.                                   table 1                   Total IgE (ng / ml)                     Mouse strain Day 6-Day 13-Day 10-                   After primary * After primary * After secondary *   OVA + PT BALB / c 400 475 750                                      (-68%) (-89%) (-91%)   OVA + PT + 3D-MLA BALB / c 125 50 65   OVA + PT C57B1 / 6 260 250 300                                      (-52%) (-60%) (-85%)   OVA + PT + 3D-MLA C57B1 / 6 125 100 45 Example II   This example demonstrates that in a mouse model, 4 shows the effect of 3D-MLA in lowering total serum IgE levels.   BALB / c or C57B1 / 6 mice, 100μg house dust allergen (HDA) + 1μg gImmunization treatment with 2% oil-in-water emulsion containing pertussis toxin (PT) ± 50 μg 3D-MLA Was performed subcutaneously. Mice received booster immunizations 14 days after primary immunization . Mice were bled 10 days after the booster immunization and tested for mouse IgE by ELISA. Serum was quantified for total IgE using a standard curve.   As can be seen from Table 2 below, consistent with the results obtained in the above experiment Simultaneous administration of house dust allergen and 3D-MLA by using different antigens The results show that serum total IgE levels are then significantly reduced.                                   Table 2                     Total IgE (ng / ml) ± SE Mouse strain Day 10-after secondary *     HDA + PT BALB / c 450 ± 72                                                 (-69%)     HDA + PT + 3D-MLA BALB / c 140 ± 40     HDA + PT C57B1 / 6 1,250 ± 201                                                 (-64%)     HDA + PT + 3D-MLA C57B1 / 6 450 ± 27 Example III   This example demonstrates that allergens are administered in multiple doses with low levels of allergens. Figure 3 shows the effect of 3D-MLA on specific IgE levels.   Brown-Norway (IgE highly reactive) rat (150-200 g, 1 5 animals per group), and 10 μg of keyhole limpet hemocyani (KLH) (obtained from Sigma Chemical). KLH is myo Settle the van, 10⁹Mixed with individual pertussis killed bacteria (obtained from Connaught Laboratories) I combined. Group A received saline containing 30 μg KLH on days 14, 21, 28 and 35 Administration, followed by 200 μl near the subcutaneous injection site on days 15, 22, 29 and 36. 0.2 ml of 0.5% triethanolamine containing g of 3D-MLA was administered. For group B, 3D- Except for using 0.5% triethanolamine dilution as control instead of MLA And the same treatment as in group A was performed. Blood was collected from all animals on days 14, 28 and 42 . PRAST assay using KLH as disc coating antigen Specific IgE was measured by a. Monoclonal bound IgE¹²⁵I mouse anti-la IgE (MARE-1). Table 3 shows the results.   Data on day 42 show that rats receiving 3D-MLA (Group A) and those receiving no 3D-MLA Significant differences were observed between the allergen-specific responses of the control rats (Group B) Are shown. Rats that did not receive 3D-MLA received antigen every time KLH was injected. It exhibited a steady increase in the level of specific IgE. In rats receiving 3D-MLA IgE levels did not increase with subsequent KLH injections. These results show that 3D-MLA By administration This prevents an increase in antigen-specific IgE during repeated exposure to allergens. Is shown.         Table 3 Drug Day 14 Day 28 * Day 42           3D-MLA 14 ± 2.0 11.5 ± 2.0 11.0 ± 2.0       Control 22 ± 2.5 35 ± 16.0 44 ± 1.5   Each value is the number of units of anti-KLH IgE antibody / ml and the standard error with respect to the average value. This is shown in FIG. * p value <0.05                                 Example IV   When MLA is administered in the same quantity and amount as 3D-MLA in Examples I to III, the same Is obtained.   The method described herein is directed to a type I transient that occurs in response to exposure to an allergen. It is effective in significantly reducing the level of IgE antibodies associated with It is even more effective in stimulating the production of gG antibodies, thereby causing hypersensitivity Risk of allergic reactions caused by allergen exposure to patients and Reduced severity.   The above examples are intended to illustrate the present invention, and all possible It is to be understood that they are not intended to include changes to used Certain modifications of the composition and / or method are also possible, yet the purpose of the present invention is to Still achieved. Such modifications are considered to be within the scope of the present invention. It is.

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Claims (1)

[Claims] 1． Methods for treating type I hypersensitivity in warm-blooded animals hypersensitive to certain allergens A monophosphoryl lipid A and a 3-deacylated mode for the warm-blooded animal. An effective amount of purified detoxified endotoxin selected from the group consisting of nophosphoryl lipid A A method comprising the administration of a pharmaceutical composition comprising the syn and a pharmaceutically acceptable carrier. 2． About 1.0 microgram to about 250 microgram of purified detoxified endotoxin 2. The method of claim 1, wherein the method is administered in an amount up to. 3． Purified detoxified endotoxin from about 25 micrograms to about 50 micrograms 2. The method of claim 1, wherein the method is administered in an amount of Four. The purified detoxified endotoxin is monophosphoryl lipid A, according to claim 1. Method. Five. The purified detoxified endotoxin is 3-deacylated monophosphoryl lipid A. The method of claim 1. 6． 2. The method of claim 1, wherein the pharmaceutical composition is administered orally. 7． 2. The method of claim 1, wherein the pharmaceutical composition is administered parenterally. 8． 2. The method of claim 1, wherein the pharmaceutical composition is administered subcutaneously. 9． To a warm-blooded animal, one or more to which the warm-blooded animal is hypersensitive 2. The method of claim 1, further comprising administering an effective amount of the allergen above. Ten. Wherein the pharmaceutical composition is administered between about 1 hour and about 1 hour after administration of the allergen. 10. The method of claim 9, wherein the method is administered. 11． 10. The method of claim 9, wherein the pharmaceutical composition is administered simultaneously with the administration of the allergen. . 12． The allergen is one or more pollen allergens, caviar allergens, Insect venom allergens, insect salivary allergens, allergens of insects or excreta , Animal scale allergens, other animal allergens, drug allergens, chemicals 10. The method of claim 9, comprising a quality allergen and a food allergen. 13. A method for decreasing IgG antibodies and increasing IgG antibodies in a warm-blooded animal, Monophosphoryl lipid A and 3-deacylated monophosphoryl for warm-blooded animals An effective amount of a purified detoxified endotoxin selected from the group consisting of lipid A; A method comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 14. About 1.0 microgram to about 250 microgram of purified detoxified endotoxin 14. The method of claim 13, wherein the method is administered in an amount up to. 15． Purified detoxified endotoxin from about 25 micrograms to about 50 micrograms 14. The method of claim 13, wherein the method is administered in an amount of 16． For warm-blooded animals, allergens, bacterial, viral and microbial antigens Further comprising the step of administering one or more compounds selected from the group consisting of 14. The method of claim 13, comprising. 17． To treat type I hypersensitivity in warm-blooded animals hypersensitive to an allergen A pharmaceutical composition comprising a monophosphoryl lipid A and a 3-deacylated monophophate. An effective amount of a purified detoxified endotoxin selected from the group consisting of sphoryl lipid A An effective amount of an allergen against which the warm-blooded animal is hypersensitive, and And a carrier. 18． The purified detoxified endotoxin is monophosphoryl lipid A, wherein the purified detoxified endotoxin is monophosphoryl lipid A. Pharmaceutical compositions. 19. The purified detoxified endotoxin is 3-deacylated monophosphoryl lipid A, A pharmaceutical composition according to claim 17.